Stent apparatus and treatment methods

ABSTRACT

There is disclosed a method of treating hypoxia in tissue of a blood vessel, the method comprising placing a stent in the vessel, the stent having a centre line which curves in three dimensions to promote the supply of oxygen from the blood flowing in the lumen of the stented vessel to the vessel wall. There is disclosed a method of treating a subject with diabetic atherosclerosis, the method comprising placing a stent in a blood vessel of the subject, the stent having a centre line which curves in three dimensions to promote the supply of oxygen from the blood flowing in the lumen of the stented vessel to the vessel wall.

This application is a continuation of U.S. patent application Ser. No.15/886,589 which was filed on Feb. 1, 2018 and is still pending. Thatapplication, in turn, is a continuation of U.S. patent application Ser.No. 14/774,575 which was filed on Sep. 10, 2015 and has now matured intoU.S. Pat. No. 9,907,679 dated Mar. 6, 2018. That application, in turn,is the entry into the national phase in the U.S. of InternationalApplication Serial No. PCT/GB2014/050822 which was filed on Mar. 14,2014 and which claims priority to U.S. Provisional Patent ApplicationSer. No. 61/794,803 which was filed on Mar. 15, 2013.

BACKGROUND

The invention relates to a stent apparatus and to a method of treatinghypoxia in vascular tissue, and to treatment and stenting methods ofsubjects with diabetes mellitus.

Blood vessel walls are comprised of living cells which are metabolicallyactive and therefore require a supply of nutrients including oxygen. Inthe absence of disease, cells in blood vessel walls receive oxygen fromthe lumen via transmural diffusion of oxygen from the blood at theinside wall of the vessel. Capillary-like microscopic vessels thatoriginate in the main vessel or another vessel and spread through theadventitia (outer layer) of the vessel, known as adventitial microvessels, provide the outer portion of the vessel tissue with a supply ofblood and consequently oxygen. Cells in tissue closer to the lumen wallof the vessel are more reliant on the transmural diffusion mechanism fortheir supply of oxygen.

Early fatty streak to advanced atherosclerotic lesions also containinflammatory cells which exhibit a high level of metabolic activityrequiring a continuous oxygen supply. Hypoxic conditions can emergeparticularly at the intima-media transition due to the development ofextra-cellular matrix in the intima as a result of previous inflammatoryepisodes in the vessel wall. In hypoxic conditions the metabolicallyactive cells express hypoxia inducible factor (HIF) which triggers adefence mechanism which attempts to restore normoxic conditions andprevent hypoxia induced necrosis and loss of tissue integrity. A keycomponent of this defence mechanism is angiogenesis.

Angiogenesis, which is the formation of new blood vessels, may betriggered by homeostatic imbalances including hypoxia. It may beclassified as physiological angiogenesis in a normal state, beingfundamental for development, reproduction and repair of blood vessels orpathological angiogenesis which is persistent due, for example, to theinability to restore normoxic conditions. Hypoxia is associated withinflammation and particularly an increased metabolic demand due tomacrophage infiltration. Vessel wall hypoxia can be accentuated due toan accumulation of fatty streaks or extracellular matrix in the intima(the innermost lining of the vessel), which limits oxygen diffusion tothe portion of the vessel wall exterior to the lesion. The resultingpresence of HIF in the nuclei of macrophages triggers the upregulationof a number of angiogenic factors including vascular endothelial growthfactor (VEGF) which initiates the development of new vessels which canimprove the local oxygen supply and allow tissue repair. Inphysiological angiogenesis, after healing has taken place, the processis reversible and angiogenesis regresses. Therefore, physiologicalangiogenesis occurs focally and is a self-limiting process.

However, pathological angiogenesis involves the persistence over asignificant time period of angiogenic stimuli, including hypoxia. Thepersistent expression of VEGF results in immature neo-vessel formationwith poorly formed microendothelium exhibiting incomplete gap junctionswhich leak red blood cells into the surrounding tissue in a processtermed intra-plaque haemorrhage. Red blood cells are rich in cholesterolso this haemorrhage leads to lipid core expansion and increased plaqueburden. Plaques which exhibit intra-plaque haemorrhage exhibit rapidprogression and are associated with an increased occurrence of clinicalevents, as discussed in the paper “Plaque neovascularization: defensemechanisms, betrayal, or a war in progress” by Moreno et al. 2012,Annals of the New York Academy of Sciences 1254 (2012) 7-17.

The above mechanisms suggest a central role for vessel wall hypoxia inthe development and progression of occlusive vascular disease. Suchplaques are commonly treated by endovascular interventions including theplacement of a stent to expand the vessel at the site of the blockageand maintain patency.

BRIEF SUMMARY

According to a first aspect of the invention, there is provided a methodof treating hypoxia in tissue of a blood vessel, the method comprisingplacing a stent in the vessel, the stent having a centre line whichcurves in three dimensions to promote the supply of oxygen from theblood flowing in the lumen of the stented vessel to the vessel wall.

Conventional stents are used to treat vessel blockages but maythemselves induce hypoxia in the vessel wall tissue which, as discussedabove, is a trigger for angiogenesis. Thus, although the stent is usedas a treatment for a blockage which may itself be caused by hypoxia andis effective in doing so by expanding the flow lumen, the stent does notmitigate the cause of the hypoxia. As a result, intimal hyperplasia is aprincipal cause of obstruction and failure of stented vessels. Thecharacteristics of intimal hyperplasia may differ in the differentsituations, but the process is generally regarded as comprising vesselwall thickening and luminal narrowing, caused by the proliferation andaccumulation of cells, including smooth muscle cells and extracellularmatrix in the intima. Measures adopted to prevent intimal hyperplasiadevelopment have included the administration of antithrombotic agents,anticoagulants, ACE inhibitors, cytotoxic agents, vascular endothelialgrowth factor and brachytherapy, but none has been successful.

Drug eluting stents, which are stents coated with anti-proliferativeagents, have attracted much attention. Improved patency is reported, ascompared with bare metal stents, however concerns remain about the longterm effects of the polymeric coatings which form the matrix into whichthe drugs are loaded. Drug elution follows a time-limited course andultimately the vessel is exposed to risk of chronic irritation or injuryfrom the stent without antiproliferative mitigation.

In a straight stent it is likely that the boundary layer at the vesselwall becomes depleted of oxygen relative to the main flow therebylimiting the transmural diffusion of the blood at the wall. It has alsobeen observed that the radially expansive force induced by the stentcauses compression of adventitial micro vessels, reducing theircross-sectional area and flow, further limiting the ability to providethe outer portion of the vessel tissue with a supply of blood and henceoxygen.

By using a stent with a centre line which curves in three dimensions,for example a stent which has a helical centre line, there is improvedintraluminal mixing and a reduction in the thickness of the boundarylayer, i.e. the boundary layer in the straight stent is thicker as thegradient of velocity close to the wall is smaller than that observed ina stent which curves in three dimensions.

The effect of the stent having a centre line which curves in threedimensions is that oxygen concentration levels immediately at the vesselwall are increased, thereby improving the transmural diffusion of oxygenfrom the blood at the inside wall of the vessel. The effect of this isto reduce the angiogenic stimulus, leading to fewer adventitial microvessels, reduced inflammation (hence reduced oxygen demand) andintra-plaque haemorrhage, slowing or possibly halting atheroscleroticprogression. Furthermore, swirling flow serves to limit intimalthickening and restenosis presumably through mechanisms includingreduction in oxygen demand (reduced inflammation) and increasing supply.

In this specification consideration has been given to the involvement ofluminal wall mass transport, as discussed further below.

Stenting can render arteries locally hypoxic. In-stent intimal crosssectional area was found to be highly correlated with adventitial microvessel number and adventitial micro vessel number can be consideredrepresentative of tissue hypoxia; it increases after stenting andhypoxia is a major stimulus for angiogenesis. Intraluminal swirling canenhance wall shear stress. But, it can additionally increaseintraluminal blood-vessel wall transport of molecular species whoseintraluminal blood-wall mass transport is fluid-phase controlled,including oxygen. Thus, swirling can enhance wall shear rate and, byvirtue of intraluminal mixing, convectively enhance intraluminalblood-vessel wall mass transport.

Based on these observations and the recognition that arterial wall masstransport derives from both adventitial micro vessel and intraluminalblood, this specification discusses quantifying the adventitial microvessel in three dimensional (3D) centre line stented and straight centreline stented arteries. Adventitial micro vessel density is found to besignificantly lower in the former vessels. In the light of the findingsabove, it is reasonable to advance the proposal that adventitial microvessel density is representative of wall hypoxia. It is furthermorereasonable to advance the hypothesis that the lesser occurrence ofintimal hyperplasia in 3D centre line stented than straight centre linestented arteries results from intraluminal mixing having enhancedblood-wall mass transport, thus mitigating stent-induced wall hypoxia.

Stenting can be expected to alter the porosity and permeability of thearterial wall. Studies of the immediate effects of arterial stenting onthe morphology of adventitial micro vessels have not been found, but ithas been found that distension of arteries by increase of theirtransmural pressure caused adventitial micro vessel cross-sections tochange from circular to elliptical, their hydraulic resistance to rise,and their flow to fall, potentially impairing wall nutrition. Stentingwill not increase adventitial micro vessel intraluminal pressure, in themanner that elevation of arterial transmural pressure in situ will. Itcould therefore affect adventitial micro vessel morphology and flow moreseverely than distension of vessels by pressurization.

It has been proposed in several patent publications, namely WO 00/32241,WO2007/082533, WO2006/032902, WO2010/041040, WO2010/041039,WO2010/041038 and WO2010/128311 (the contents of all of which areincorporated herein by reference), that intimal hyperplasia can besignificantly reduced by using a stent having a centre line curving inthree dimensions.

However, these publications do not disclose that stenting can renderarteries locally hypoxic, nor that a stent with a centre line curving inthree dimensions can inhibit hypoxia, nor that additional micro vesselnumbers can be considered representative of hypoxia. Stents are usuallyprovided in a collapsed condition until they have been located at thetreatment site, where they are expanded. The stent used in the methodsdescribed herein may be balloon-expandable. Thus, the stent may beprovided with a balloon to expand it from the collapsed to the expandedcondition. The stent may be made of a shape memory material, such as ashape memory alloy, for example nitinol. Stents made of shape memorymaterials may be delivered in a collapsed condition and then expanded,for example by removing an external radial constraint, so that theyexpand at the treatment site. A shape memory stent may in somecircumstances be provided with a balloon to assist expansion.

When the stent of the invention is expanded ex vivo it will generallyhave a centre line which curves in three dimensions. When it is expandedin vivo, it will to some extent be constrained from adopting its fullyexpanded ex vivo geometry due to the counteracting constraining actionof the vessel. Whilst this may to some extent reduce the threedimensional curvature of the stent, three dimensional curvature is stillmaintained.

Preferably the stent when expanded ex vivo has a helical centre line.When the stent is expanded in vivo the constraining action of the vesselwill to some extent modify the helical geometry, for example reducingthe curvature. This can result for example from a reduction in thehelical amplitude and/or an increase in the pitch. There may then bevariations in the curvature over the length of the stent, due tovariations in the helical amplitude and/or helical pitch.

The stent may impose its three dimensional geometry on the vessel. Thevessel may be caused by the stent to adopt the same three dimensionallycurved centre line as the stent. Known stents which adapt their shape toexisting geometry could just be reproducing the geometry whichoriginally led to the occurrence of a lesion or, even worse, could beaccentuating conditions which led to the occurrence of the lesion.

The recognition in this specification that conventional stentscontribute to the phenomenon of hypoxia and that the use of stents witha centre line curving in three dimensions can treat hypoxia, opens upthe use of particular stent geometries with certain patient groups.

According to a second aspect of the invention, there is provided amethod of treating a subject with diabetic atherosclerosis, the methodcomprising placing a stent in a blood vessel of the subject, the stenthaving a centre line which curves in three dimensions to promote thesupply of oxygen from the blood flowing in the lumen of the stentedvessel to the vessel wall.

Subjects with diabetes mellitus often develop diabetic atherosclerosis.They can suffer from flow limiting atherosclerotic disease. Acontributing factor to this development is hypoxia in the vessel tissue.By using a stent which itself treats or inhibits hypoxia, restenosis inpatients with diabetic atherosclerosis or diabetes mellitus may bereduced.

According to a third aspect of the invention, there is provided a methodof treating hypoxia in tissue of a blood vessel in which a stent isalready disposed, the method comprising placing an expandable member ina collapsed condition thereof radially inwardly of the stent in thevessel, and expanding the expandable member from the collapsed conditionto an expanded condition in which the expandable member has a centreline which curves in three dimensions, so as to cause the stent to adopta shape in which it also has a centre line which curves in threedimensions.

Once the stent has been caused to adopt a shape in which it has a centreline which curves in three dimensions, this alters the shape of the flowlumen of the vessel to promote the supply of oxygen from the bloodflowing in the lumen of the stented vessel to the vessel wall. Swirlflow may be promoted in the flow lumen. The thickness of the boundarylayer may be reduced and mass transport, particularly oxygen, betweenthe blood and the vessel wall may be increased. This can treat hypoxiain the vessel wall.

It will be understood that post dilation of a stent with an expandablemember may be carried out to treat hypoxia.

The expandable member may be a balloon.

The centre line of the stent and that of the expandable member after theexpandable member has been expanded from the collapsed condition to theexpanded condition may be the same.

The centre line of the expandable member when expanded ex vivo to theexpanded condition may be a helical centre line. When the expandablemember is expanded in the stent there may be resistance from the stentand the vessel wall with the result that the curvature along the lengthof the stent may vary. For example, the curvature may be reducedcompared to that which the expandable member would adopt if expanded exvivo. The helical amplitude may be decreased and/or the pitch may beincreased, such variations in either of these parameters resulting inreduced curvature in vivo compared to ex vivo.

After the stent has been caused to adopt a shape in which it has acentre line which curves in three dimensions, the expandable member maybe collapsed and removed. The stent may retain the shape imparted to itby the expandable member. The stent may retain the shape by having beenplastically deformed.

The stent which is to be expanded may comprise stainless steel or cobaltchromium, magnesium based alloys or biodegradable polymeric materials.It will be understood that other plastically deformable materials may beused.

According to a fourth aspect of the invention, there is provided amethod of treating a subject for whom blood vessel stenting isindicated, the method comprising placing a drug eluting stent in thevessel, the stent having a centre line which curves in three dimensions.

The invention also provides a drug eluting stent having a centre linewhich curves in three dimensions.

Swirl flow may be promoted in the flow lumen of the vessel stented withthe drug eluting stent. The thickness of the boundary layer may bereduced.

Secondary flow (i.e. the component of the flow transverse to the mainaxial flow) can move the drug from the immediate vicinity of the stentto the areas between the members, such as struts, which form the stent.Thus, the drug can act to inhibit intimal growth more effectively inthese areas of the vessel wall which are not in contact with the stent.This can be contrasted with conventional straight stents where there isrelatively little secondary flow so the drug eluted from the stentreaches these areas to a lesser extent.

The vessel may be a main vessel and a branch vessel may extend from themain vessel, and the stent may be placed in the main vessel so that atleast a portion of the stent extends in the main vessel upstream of thebranch vessel. This allows the stent to influence the flow upstream ofthe branch vessel, which may also be considered as a collateral ordaughter vessel). Secondary flow in the main vessel can allow the drugto be swept into the bulk flow from the drug eluting stent and carrieddownstream into the branch vessel. After stenting the angle between themain branch and the branch vessel often changes, which can result in thedevelopment of a stenosis at the proximal end of the collateral vessel.The drug which is now in the bulk flow can reduce the propensity forthis proximal disease in the collateral vessel to develop. The branchvessel may be unstented. The method may comprise stenting the branchvessel. A second stent in the branch vessel may not be a drug elutingstent. It may be for example a bare metal stent. Secondary flow in themain vessel can allow the drug to be swept into the bulk flow from thedrug eluting stent and carried downstream into the branch vessel, whereit can act in the region of the second stent to provide a therapeuticbenefit to the stented branch vessel. It may for example inhibit intimalingrowth in the branch vessel.

The stent in the main vessel may extend therein downstream of the branchvessel. The stent may therefore extend both upstream and downstream ofthe junction with the branch vessel. Flow from the main vessel may enterthe branch vessel by passing though openings in the stent, such openingsbeing conventional in stents.

According to a fifth aspect of the invention, there is provided a methodof treating a subject for whom blood vessel stenting is indicated,wherein the vessel is a main vessel and a branch vessel extends from themain vessel, the method comprising placing the stent in the main vesselso that at least a portion of the stent extends in the main vesselupstream of the branch vessel, and the stent having a centre line whichcurves in three dimensions.

According to a sixth aspect of the invention, there is provided a methodof treating a blood vessel branching from another vessel having a stenttherein with at least a portion of the stent being upstream of thebranch vessel, the method comprising placing an expandable member in acollapsed condition thereof radially inwardly of the stent in thevessel, and expanding the expandable member from the collapsed conditionto an expanded condition in which the expandable member has a centreline which curves in three dimensions, so as to cause the stent to adopta shape in which it also has a centre line which curves in threedimensions.

By providing a stent having a centre line which curves in threedimensions in a main vessel so that at least a portion of the stentextends in the main vessel upstream of a branch vessel, or by causing astent already in a main vessel to adopt a shape in which it has a centreline which curves in three dimensions, secondary flow in the branchvessel may be promoted to provide a therapeutic benefit to the branchvessel. The use of a conventional stent in a main vessel can result in achange of angle between the main vessel and the branch vessel, which maylead to a reduced flow rate and the development of a stenosis in thebranch vessel. The promotion of secondary flow in the main branchupstream of the branch vessel may increase flow rate in the branchvessel and may inhibit development of a stenosis in the branch vessel.

According to a seventh aspect of the invention, there is provided amethod of treating a subject for whom blood vessel stenting isindicated, comprising identifying a treatment site, determining whethernatural vessel geometry at that treatment site will impart right-handedswirl flow or left-handed swirl flow to the blood flow along the vessel,and selecting for placement at the treatment site a stent having acentre line with three-dimensional curvature, the selected stent havingright-handed curvature if the vessel has been determined to naturallyimpart right handed swirl flow and the selected stent having left-handedcurvature if the vessel has been determined to naturally impartleft-handed swirl flow.

The invention also provides apparatus comprising a plurality of stentseach having a centre line curving in three dimensions, the plurality ofstents including at least one stent with a centre line havingright-handed curvature and at least one stent with a centre line havingleft-handed curvature.

The stent with right-handed curvature may be for use in a vessel whichhas been determined to naturally impart right handed swirl flow, and thestent with left-handed curvature may be for use in a vessel which hasbeen determined to naturally impart left-handed swirl flow. When aclinician wishes to stent a vessel, the apparatus provides a choice ofusing a right-hand curved stent or a left-hand curved stent. A stent maybe selected as appropriate to complement the natural direction of swirland not to tend to cancel it.

The choice can be made based on whether the site at which the stent isto be located is one where there will be natural right-handed swirl flowor natural left-handed swirl flow of the blood flow along the vessel.The handedness of the swirl flow can be determined by scanning thevessel by known scanning methods, such as X-ray scanning transversecolour Doppler ultrasound, Computer Tomography (CT), Magnetic ResonanceImaging (MRI) or C-Arm Cone Beam CT, and then the appropriate stent maybe selected. Alternatively, the handedness can be determined byreference to the following examples.

Examples of vessels which commonly have right-handed curvature are theleft iliac artery, the left iliac vein, the left femoropopliteal artery,the left femoropopliteal vein, the left coronary artery, and the leftanterior descending artery. Examples of vessels which commonly haveleft-handed curvature are the right iliac artery, the right iliac vein,the right femoropopliteal artery, the left coronary circumflex and theright femoropopliteal vein.

The above examples are not exhaustive and of course there are othertreatment sites which can benefit from selecting a stent with threedimensional curvature of the appropriate curvature. It is alsounderstood that handedness of specific vessels may vary from patient topatient.

Commonly where a vessel bifurcates, the geometry of the bifurcation issuch that the flow downstream of the bifurcation in both branches isswirling flow.

Therefore, a stent placed downstream of a bifurcation can be selectedwith the appropriate three dimensional curvature handedness.

Right-handed curvature of the centre line means clockwise curvature andleft-handed curvature means counter-clockwise curvature. Clockwisecurvature involves clockwise rotation of the centre line of the stent asviewed in a direction receding away from the viewer, andcounter-clockwise curvature involves counterclockwise rotation of thecentre line of the stent as viewed in a direction receding away from theviewer.

The apparatus may comprise a plurality of right-handed curved stents anda plurality of left-handed curved stents. The right-handed curved stentsmay be all the same size, or there may be different sizes. Theleft-handed curved stents may be all the same size, or there may bedifferent sizes. The diameters and/or lengths of the stents may bedifferent.

BRIEF DESCRIPTION OF THE DRAWINGS

Certain preferred embodiments of the invention will now be described byway of example and with reference to the accompanying drawings, inwhich:

FIG. 1 is a perspective view of an embodiment of a helical stent inaccordance with the invention;

FIG. 2 is a perspective view illustrating flow in a straight stent;

FIG. 3 is a perspective view illustrating flow in a helical stent;

FIG. 4 shows a pair of porcine carotid arteries implanted with straightand helical stents;

FIG. 5 shows a computational fluid dynamics (CFD) simulation of flows inporcine carotid arteries stented with straight and helical stents;

FIGS. 6a and 6b show transverse histology sections of proximal, middleand distal segments of carotid arteries one month after stentdeployment; FIGS. 7a and 7b show graphs of intima/media thickness ratiosfor helical stented and straight stented carotid arteries, respectively;

FIGS. 8a to 8d show graphs of adventitial micro vessel counts at distal,middle and proximal locations, and the average of the distal, middle andproximal counts, respectively, for helical stented and straight stentedcarotid arteries;

FIG. 9 is a perspective view of a helical stent with right-handedcurvature;

FIG. 10 is a perspective view of a helical stent with left-handedcurvature;

FIG. 11 shows perspective views of a drug eluting helical stent at avessel branch, with a straight stent in a collateral vessel;

FIG. 12 shows perspective views of a drug eluting helical stent at avessel branch, without there being any stent in a collateral vessel; and

FIG. 13 shows a perspective view of a bare metal helical stent at avessel branch, without there being any stent in a collateral vessel.

DETAILED DESCRIPTION

FIG. 1 shows a self-expanding stent 1 made from a shape memory alloy, inthis case nitinol. The stent 1 has a helical centre line 2. The stent 1comprises struts 22.

FIGS. 2 and 3 show the flow in straight and helical stented arteriesrespectively. The flow lines 3 in the straight stented artery shown inFIG. 2 are generally straight, whereas the flow lines 3 in the helicalstented artery show a swirling pattern illustrating how fluid at thevessel wall is transported towards the centre of the flow and viceversa.

FIG. 4 shows an angiogram image of a pair of porcine carotid arteries 20which have been stented. The straight stented artery 4 is shown on theright hand side, having downstream and upstream ends 6. The helicalstented artery 5 is shown on the left hand side, having downstream andupstream ends 7. It can be seen that the straight stented artery issubstantially straight and that the helical stented artery exhibitsthree dimensional curvature.

FIG. 5 shows vector diagrams produced by a computational fluid dynamicsimulation of flow in stented arteries. At the upper left of the drawingthe porcine carotid arteries are shown, and portions thereof are shownto an enlarged scale on the right of the drawing. The straight stentedartery is indicated at reference 4 and the helical stented artery isindicated at reference 5. The vectors themselves are shown as “brush”like images, with each “bristle” of the brush being a flow vector. Eachimage represents the flow across the transverse section of therespective artery at the region shown. Each vector shows the so-calledsecondary component of the flow field, i.e. the component of flow at therelevant point on the transverse section which is perpendicular to thelongitudinal axis of the artery, along which there is the primary flow.It will be seen that the helical stented artery 5 exhibits a distinctiveswirling pattern and that this swirl flow involves relatively highsecondary flow velocities, indicated by the relatively large length ofthe vectors, near the inside (medial) wall of the artery. On the otherhand, the near wall vector length for the straight stented artery 4 isrelatively small, indicating slower secondary near wall flow velocities.

Transverse sections of segments of the carotid arteries one month afterimplantation are shown in FIG. 6. FIG. 6a shows a proximal section 8, amiddle section 9 and a distal section 10 for the straight stented artery4, FIG. 6b shows a proximal section 11, a middle section 12 and a distalsection 13 for the helical stented artery 5.

FIG. 9 shows a stent 1 with right-handed curvature, for use in a vesselwhich has been determined to naturally impart right handed swirl flow,and FIG. 10 shows a stent 1 with left-handed curvature for use in avessel which has been determined to naturally impart left-handed swirlflow. In FIG. 9 an arrow indicates the clockwise, right-handed curvatureand in FIG. 10 an arrow indicates the counter clockwise, left-handedcurvature. The pair of stents form a kit, or apparatus, from which anappropriate stent may be selected. In such a kit, additional right- andleft-handed curvature stents may be provided. When a clinician wishes tostent a vessel, the kit provides a choice of using a right-hand curvedstent or a left-hand curved stent. A stent may be selected asappropriate to complement the natural direction of swirl and not to tendto cancel it.

FIG. 11 shows a drug eluting stent 1 having a centre line which curvesin three dimensions. The stent has struts 22 and is placed in a mainvessel 20. The direction of flow of blood in the main vessel 20 isindicated by the arrows, i.e. the blood inflow is at the lower end ofthe vessel as seen in the Figure, and the blood outflow is at the upperend of the vessel. Because the stent has a centre line which curves inthree dimensions, it imposes a corresponding curved centre line on themain vessel 20. The effect is to promote swirling flow as indicated bythe flow lines 3.

A branch vessel 21 branches from the main vessel 22. This is shownstented with a conventional stent 15 having a straight centre line. Thesecondary flow over the struts 22 which are coated with a drug causesthe drug to be moved from the immediate vicinity of each strut to theareas between the struts. This may inhibit intimal growth in thoseareas, and therefore intimal growth overall. In addition, the drug maybe carried by the secondary flow into the branch vessel 21. The stent 15in the branch vessel is a non-drug eluting stent. However, the drugcarried from the main vessel 20 can provide a therapeutic benefit in thebranch vessel 21 where it is stented by the stent 15. Finally, thesecondary flow in the main vessel may increase the flow into the branchvessel 21 (compared to a situation where the main vessel was stentedwith a straight stent), promoting secondary flow in the branch vesseland hence providing a therapeutic benefit.

FIG. 12 shows a similar arrangement to FIG. 11, with the differencebeing that there is no stent in the branch vessel 21. In this case theswirl flow again allows the drug on the struts 22 of the stent 1 in themain vessel 20 to be conveyed to the areas between the struts. Thesecondary flow in the main vessel assists conveyance of the drug intothe secondary vessel, where it may inhibit the development of a stenosisat the proximal end of the branch vessel. The secondary flow in the mainvessel may increase the flow generally (irrespective of the presence ofthe drug) to the branch vessel 20 and thereby also aid perfusion andinhibit stenosis development.

FIG. 13 shows a stent 1 having struts 22 in a main vessel 20. The stent1 is a bare metal stent (i.e. it is not a drug eluting stent) having acentre line which curves in three dimensions. This increases secondaryflow in the main vessel compared to a situation where the main vessel isprovided with a straight stent. The secondary flow may act to increasethe flow into the branch vessel 21, which may aid perfusion and inhibitstenosis development in the branch vessel 21.

The stent shown in FIG. 13 may be constructed to have a helical geometrywhen in an expanded condition from the outset. Therefore, it may be aballoon expandable stent or a self-expanding stent comprising a shapememory material, in each case being designed to adopt a helical shapewhen expanded. Alternatively, the stent shown in FIG. 13 may have beenalready installed in the vessel, and it has then been post dilated usinga helical expandable member, such as a balloon, so as to adopt thehelical shape shown in FIG. 3. This may provide a way of treating astenosis which has developed in the branch vessel 21 following theinitial straight stent placement in the main vessel 20. The shape of thestent in the main vessel is modified to have a centre line which curvesin three dimensions, thereby providing this treatment.

Example

A study was undertaken using ten pigs. In each animal a straight stentwas placed in one of the carotid arteries and a helical stent was placedin the contralateral carotid artery. Ultrasound was used to measure thearteries for stent diameter selection and the stents were oversized withrespect to the internal artery diameter. Five of the straight stentswere deployed in a right artery and five in the left, and five of thehelical centre line stents were deployed in the left carotid artery andfive in the right carotid artery. Digital subtraction angiography, usinga contrast agent, was performed immediately after stent deployment toassess vessel geometry. An example is shown in FIG. 4. In addition, asmall bolus of contrast agent was injected intraluminally to assesswhether there was swirling. Doppler ultrasound was used to detectswirling flow in the helically stented artery. In the contralateralstraight stented vessel, axial passage of the contrast agent wasobserved.

Implantation of both the straight stent and the helical stent causedimmediate deformation of the vessels, but the latter stent causedadditional helical deformation of vessels and swirling of intraluminalflow. The changes persisted to the end of the study at 30 days. In fact,the maximum stent amplitude increased from the time of implantation tothe time of termination at 30 days.

The amplitude ratio is the helical amplitude divided by the internaldiameter of the stent. The average maximum amplitude ratio for the tenhelically stented arteries was 0.18 with a standard deviation of 0.11 atimplantation and 0.31 with a standard deviation of 0.14 at day 30.

After termination at 30 days transverse sections of proximal(downstream), middle and distal (upstream) segments of the carotidarteries were studied. An example of a straight stented artery, showingthese three segments, is shown in FIG. 6a , and an example of ahelically stented artery, having these three segments, is shown in FIG.6 b.

Histological study showed the neointima to consist of smooth musclecells in an organised extra-cellular matrix, with uniform endothelialcell coverage and no difference between the straight centre line stentedand helical centre line stented groups, with respect to inflammation,mural thrombosis, or re-endothelialization scorings. Transverse sectionsfrom the proximal, middle and distal segments of the stented carotidarteries showed intimal thickness to be significantly less in thehelical centre line stented than straight centre line stented vessels,as seen in FIG. 6. Averaged over the three segments, intimal thicknesswas 45% lower in the helical centre line stented artery than in thestraight centre line stented artery.

In a healthy artery or vein the intima forms the innermost layer. It ismade up of one layer of endothelial cells which are in direct contactwith the blood flow and internal elastic membrane. Radially outwardly ofthe intima is a middle layer known as the media. In this example theintima/media thickness ratio was investigated.

The results are shown in FIG. 7. FIG. 7a shows a graph of intima/mediathickness ratios for the helical stented artery and FIG. 7b shows agraph of intima/media thickness ratios for the straight stented artery.Comparing FIG. 7a showing the helically stented artery with FIG. 7bshowing the straight stented artery, it will be seen that theintima/media thickness ratio was significantly higher overall in thestraight centre line stented than the helical centre line stentedvessels. In addition, the ratio was significantly lower in the distalthan proximal or middle segments in the helical centre line stentedvessels. Thus, the histology revealed the intima/media thickness ratioand intimal hyperplasia to be significantly lower in helical centre linestented arteries than in straight centre line stented arteries.

The number of adventitial micro vessels was determined for each sample,for both the helical centre line stented and straight stented arteries.Adventitial micro vessel number was not correlated with sectionthickness. The results shown in FIG. 8 therefore are presented asadventitial micro vessel density (number of micro vessels per unitadventitial area). FIG. 8a shows a graph of adventitial micro vesselcounts at the distal location for the helical (3D) stented and straightstented carotid arteries, FIG. 8b shows a graph of adventitial microvessel counts at the middle location for the helical (3D) stented andstraight stented carotid arteries, FIG. 8c shows a graph of adventitialmicro vessel counts at the proximal location for the helical (3D)stented and straight stented carotid arteries, and FIG. 8d shows a graphof the average of the distal, middle and proximal adventitial microvessel counts, for helical (3D) stented and straight stented carotidarteries. Considering the averaged results for the proximal, middle anddistal segments shown in FIG. 8b , adventitial micro vessel density wassignificantly lower in the helical centre line stented than straightcentre line stented arteries, the values being: helical centre linestented 130.8±7.2; straight centre line stented 216.3±19.1. Thedifference between helical centre line stented and straight centre linestented vessels was pronounced in the proximal and middle segments, butnot significant in the distal segments.

It was found that adventitial micro vessel density was significantlylower in the helical centre line stented vessels than in the straightcentre line stented arteries. This supports the proposal thatadventitial micro vessel density is representative of wall hypoxia. Thelesser occurrence of intimal hyperplasia in the helical centre linestented arteries than in the straight centre line stent arteriesresulted from improved intraluminal mixing and hence enhanced blood-wallmass transport, thereby reducing the effect of stent-induced wallhypoxia.

We also consider changes in the different (proximal, middle and distal)segments of the straight- and helical centre line stented arteries. Theproximal segment is at the upstream end of the artery and the distalsegment is at the downstream end. The flow can be expected to developwith distance along both types of stented artery. In the straight centreline case, presuming the vessel to be straight, circular, uniform incross-section and unbranched, wall shear stress will fall with distancealong it, due to the cylindrical shape imposed by the stent and hencethe development of a thicker boundary layer where blood flow speeds areslow or even stagnant. In the helical centre line case, the flow willadditionally depend on the curvature of the helical vessel and, assumingthe diameter and other geometric parameters to remain constant along thevessel, wall shear stress will, in contrast with the straight case, risewith distance as swirl flow develops, with the consequent reduction inthe thickness of the boundary layer. Assuming that increase of wallshear stress lessens intimal hyperplasia, the lower intima/mediathickness ratio in the distal than proximal and middle segments of thehelical centre line stented vessels, as shown in FIGS. 7a and 7b ,could, therefore, relate to a rise of wall shear stress associated withdevelopment of the flow.

Measurements from angiograms show, however, that both the helical- andstraight-stented carotid arteries taper in the downstream direction (theproximal to distal direction), their cross-sectional areas decreasing onaverage from 24 mm² to 20 mm² between the proximal and distal segments.Provided the mass flux remained essentially constant along the vessels,such tapering would increase wall shear stress proceeding downstream andcould therefore contribute to explaining the lower intima/mediathickness ratio seen in the distal than proximal and middle segments ofhelical centre line stented carotid arteries. Moreover, it could helpexplain the tendency for the intima/media thickness ratio to belower—rather than predicted higher—proceeding from the proximal todistal segments of straight centre line stented vessels, as seen in FIG.7.

There is, however, evidence supportive of the hypothesis that helicalcentre line stented carotid arteries were less hypoxic than straightcentre line stented vessels, namely that supplementary oxygen reducedthe severity of intimal hyperplasia after arterial stenting in animals.It is clear that, whether the section considered is proximal, middle ordistal, the density of adventitial micro vessels, which isrepresentative of hypoxia, is greater for straight stented vessels thanfor helically stented vessels. The average adventitial micro vesselcounts shown in FIG. 8d show a higher average adventitial micro vesseldensity in the straight stented arteries compared to the “helically”stented arteries.

1. Apparatus comprising a plurality of stents each having a centre linecurving in three dimensions, the plurality of stents including at leastone stent with a centre line having right-handed curvature and at leastone stent with a centre line having left-handed curvature.
 2. Apparatusas claimed in claim 1, comprising a plurality of right-handed curvedstents and a plurality of left-handed curved stents.
 3. A method oftreating hypoxia in tissue of a blood vessel, the method comprisingplacing a stent in the vessel, the stent having a centre line whichcurves in three dimensions to promote the supply of oxygen from theblood flowing in the lumen of the stented vessel to the vessel wall. 4.A method of treating a subject with diabetic atherosclerosis, the methodcomprising placing a stent in a blood vessel of the subject, the stenthaving a centre line which curves in three dimensions to promote thesupply of oxygen from the blood flowing in the lumen of the stentedvessel to the vessel wall.
 5. A method as claimed in claim 3 or 4,wherein the stent when expanded ex vivo has a helical centre line.
 6. Amethod as claimed in claim 3, 4 or 5, wherein the stent comprises ashape memory material.
 7. A method as claimed in claim 3, 4 or 5,wherein the stent comprises a plastically deformable material.
 8. Amethod as claimed in any of claims 3 to 7, wherein the stent is expandedwith the aid of a balloon.
 9. A method of treating hypoxia in tissue ofa blood vessel in which a stent is already disposed, the methodcomprising placing an expandable member in a collapsed condition thereofradially inwardly of the stent in the vessel, and expanding theexpandable member from the collapsed condition to an expanded conditionin which the expandable member has a centre line which curves in threedimensions, so as to cause the stent to adopt a shape in which it alsohas a centre line which curves in three dimensions.
 10. A method asclaimed in claim 9, wherein the expandable member is a balloon.
 11. Amethod as claimed in claim 9 or 10, wherein the centre line of theexpandable member when expanded ex vivo to the expanded condition is ahelical centre line.
 12. A method as claimed in claim 9, 10 or 11,wherein the stent comprises a plastically deformable material.
 13. Amethod of treating a subject for whom blood vessel stenting isindicated, the method comprising placing a drug eluting stent in thevessel, the stent having a centre line which curves in three dimensions.14. A method as claimed in claim 13, wherein the vessel is a main vesseland a branch vessel extends from the main vessel, and wherein the stentis placed in the main vessel so that at least a portion of the stentextends in the main vessel upstream of the branch vessel.
 15. A methodas claimed in claim 14, comprising stenting the branch vessel.
 16. Amethod of treating a subject for whom blood vessel stenting isindicated, wherein the vessel is a main vessel and a branch vesselextends from the main vessel, the method comprising placing the stent inthe main vessel so that at least a portion of the stent extends in themain vessel upstream of the branch vessel, and the stent having a centreline which curves in three dimensions.
 17. A method of treating a bloodvessel branching from another vessel having a stent therein with atleast a portion of the stent being upstream of the branch vessel, themethod comprising placing an expandable member in a collapsed conditionthereof radially inwardly of the stent in the vessel, and expanding theexpandable member from the collapsed condition to an expanded conditionin which the expandable member has a centre line which curves in threedimensions, so as to cause the stent to adopt a shape in which it alsohas a centre line which curves in three dimensions.
 18. A method asclaimed in claim 17, wherein the stent comprises a plasticallydeformable material.
 19. A drug eluting stent having a centre line whichcurves in three dimensions.
 20. A method of treating a subject for whomblood vessel stenting is indicated, comprising identifying a treatmentsite, determining whether natural vessel geometry at that treatment sitewill impart right-handed swirl flow or left-handed swirl flow to theblood flow along the vessel, and selecting for placement at thetreatment site a stent having a centre line with three-dimensionalcurvature, the selected stent having right-handed curvature if thevessel has been determined to naturally impart right handed swirl flowand the selected stent having left-handed curvature if the vessel hasbeen determined to naturally impart left-handed swirl flow.